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	Identification of UDP-glucuronosyltransferases involved in human hepatic glucuronidation of diethylstilbestrol
	Zhu LL(朱亮亮) ; Ge GB(葛广波) ; Liu HX(刘慧鑫) ; Yang L(杨凌)
	2010-09-04
会议名称	9th international meeting of the international-society-for-the-study-of-xenobiotics(issx）
会议日期	2010-9-4
会议地点	土耳其
页码	62/2
通讯作者	杨凌
中文摘要	diethylstilbestrol (des), a synthetic estrogen, was once prescribed to pregnant women to reduce the risk of pregnancy complications and losses, and now in treatment for breast and prostate cancers and locally for estrogen deficiencies. it has been proved that des can cause a series of cancers and other health problems. previous studies revealed that monoglucuronide was a major metabolite in human [1], and this metabolism is generally believed to be a detoxification process [2]. however, glucuronidation metabolism pathway of des in human remained poorly understood. this study was focused on hepatic glucuronidation of des by human liver microsomes (hlms) and a panel of 12 recombinant udp- glucuronosyltransferases (ugt) including ugt1a1, 1a3, 1a4, 1a6, 1a7, 1a8, 1a9, 1a10, 2b4, 2b7, 2b15, and 2b17. des was extensively glucuronidated in pooled hlms, and one monoglucuronide was observed by hplc and lc/ms/ms. hlms exhibited substrate inhibition kinetics for des, with km, ksi, and vmax value of 2.44 μm, 19.4 μm and 1.12 nmol/min/mg protein, respectively. assays with 12 recombinant ugt isoforms revealed that ugt1a1, 1a3, 1a8 and 2b7 can catalyze the des glucuronide formation. each isoform displayed substrate inhibition kinetics, and ugt2b7 showed the highest udp-glucuronosyltransferases activity towards des with km, ksi, and vmax value of 2.16 μm, 12.9 μm and 0.31 nmol/min/mg protein, respectively (similar to that of pooled hlms). des glucuronidation (2 μm) in hlms from 11 donors correlated strongly (r=0.90, p<0.001) with azt glucuronidation (a probe reaction for ugt2b7 activity), while no significant correlation (r=0.52, p=0.10) was observed with estradiol-3-glucuronidation (a probe reaction for ugt1a1 activity). in chemical inhibition study, a series of inhibitors including estradiol, mefenamic acid, and androsterone showed similar inhibitory effects towards hlms and ugt2b7 mediated glucuronidation. in summary, this study characterized the hepatic glucuronidation pathway of des, during which ugt2b7 played an important role.
会议主办者	国际药物代谢学会
学科主题	物理化学
语种	中文
WOS记录号	WOS:000281147700112
内容类型	会议论文
源URL	[http://159.226.238.44/handle/321008/114316]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
推荐引用方式 GB/T 7714	Zhu LL,Ge GB,Liu HX,et al. Identification of UDP-glucuronosyltransferases involved in human hepatic glucuronidation of diethylstilbestrol[C]. 见:9th international meeting of the international-society-for-the-study-of-xenobiotics(issx）. 土耳其. 2010-9-4.

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